Arterial dysfunction, characterized by vascular stiffening and endothelial impairment, is associated with co-morbid complications including atherosclerosis. Though arterial dysfunction is known to be greater at older ages, little is known about why some individuals manifest vascular impairment when relatively young and others retain adequate vascular function at relatively older ages. We propose that genetic factors are among the primary precursors of premature vascular dysfunction. We will examine this hypothesis in families from the Johns Hopkins Sibling and Family Heart Study, a study of families identified from a proband with premature coronary artery disease (CAD). We have characterized over 2500 two-generational relatives, now aged 21 to 78 years. All have baseline measurements of atherosclerosis risk factors, attendant lifestyles, and inflammatory biomarkers. All subjects have had high throughput genotyping of 4783 single nucleotide polymorphisms (SNPs) in 190 candidate genes involved in vascular function, including inflammation, cell signaling, vascular tone, and vascular structure. All are now fully genotyped with a dense 1,000,000 genome wide SNP scan through the NHLBI STAMPEED program. We propose to study 1500 participants without clinically manifest atherosclerotic vascular disease to determine two age-related vascular function phenotypes (1) carotid artery stiffness, and (2) post-ischemic brachial artery flow-mediated dilatation. We will determine the extent to which polymorphisms in candidate genes are associated with premature vascular dysfunction, independent of risk factors for atherosclerosis and inflammatory marker levels. Further, we will also examine which novel genetic loci in the genome wide SNP scan are associated with the phenotypes of premature vascular dysfunction and preserved vascular function in older subjects. We will replicate our findings in two population-based studies (the Multi-Ethnic Study of Atherosclerosis for whites and African Americans, and the Framingham Heart Study for whites). This study should provide information specifically related to the role of genes in age-related vascular dysfunction in white and African American families with a known propensity toward premature coronary artery disease. PUBLIC HEALTH RELEVANCE: Chronic inflammation is thought to prematurely make arteries stiffer and function poorly, leading to heart attacks and heart failure. We are testing whether these disease processes are associated with known and newly discovered genes in families with history of premature coronary diseases. Our results will help us understand what genes and mechanisms lead to premature artery diseases.